Exonic microdeletions of the gephyrin gene impair GABAergic synaptic inhibition in patients with idiopathic generalized epilepsy

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Item Type:	Article
Title:	Exonic microdeletions of the gephyrin gene impair GABAergic synaptic inhibition in patients with idiopathic generalized epilepsy
Creators Name:	Dejanovic, B., Lal, D., Catarino, C.B., Arjune, S., Belaidi, A.A., Trucks, H., Vollmar, C., Surges, R., Kunz, W.S., Motameny, S., Altmüller, J., Köhler, A., Neubauer, B.A., Nürnberg, P., Noachtar, S., Schwarz, G. and Sander, T.
Abstract:	Gephyrin is a postsynaptic scaffolding protein, essential for the clustering of glycine and γ-aminobutyric acid type-A receptors (GABA(A)Rs) at inhibitory synapses. An impairment of GABAergic synaptic inhibition represents a key pathway of epileptogenesis. Recently, exonic microdeletions in the gephyrin (GPHN) gene have been associated with neurodevelopmental disorders including autism spectrum disorder, schizophrenia and epileptic seizures. Here we report the identification of novel exonic GPHN microdeletions in two patients with idiopathic generalized epilepsy (IGE), representing the most common group of genetically determined epilepsies. The identified GPHN microdeletions involve exons 5–9 (Δ5–9) and 2–3 (Δ2–3), both affecting the gephyrin G-domain. Molecular characterization of the GPHN Δ5–9 variant demonstrated that it perturbs the clustering of regular gephyrin at inhibitory synapses in cultured mouse hippocampal neurons in a dominant-negative manner, resulting in a significant loss of γ(2)-subunit containing GABA(A)Rs. GPHN Δ2–3 causes a frameshift resulting in a premature stop codon (p.V22Gfs*7) leading to haplo-insufficiency of the gene. Our results demonstrate that structural exonic microdeletions affecting the GPHN gene constitute a rare genetic risk factor for IGE and other neuropsychiatric disorders by an impairment of the GABAergic inhibitory synaptic transmission.
Keywords:	Idiopathic Generalized Epilepsy, Microdeletion, GPHN, Gephyrin
Source:	Neurobiology of Disease
ISSN:	0969-9961
Publisher:	Elsevier
Volume:	67
Page Range:	88-96
Date:	July 2014
Official Publication:	https://doi.org/10.1016/j.nbd.2014.02.001
PubMed:	View item in PubMed

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